As the successful treatment of cancer remains a challenging goal, research into novel, selective, and less toxic chemotherapeutic agents is gathering pace (Bassou, 2006, J Lipid Res; Bell, Inhibitors of farnesyltransferase: A rational approach to cancer chemotherapy? J. Med. Chem. 2004, 8, 1869-1878; Doll, et al., Farnesyltransferase inhibitors as anticancer agents: critical crossroads. Curr. Opin. Drug Discov. Devel. 2004, 7, 478-486). Increased understanding of the cellular processes that lead to cancer has identified additional targets for the design of such chemotherapeutics. Ras, the protein product of the ras oncogene, is a small GTPase that is important in signal transduction, cell growth, and cell proliferation (Shields, J. M.; Pruitt, K.; McFall, A.; Shaub, A.; Der, C. J. Understanding Ras: “It ain't over 'til it's over.” Trends Cell Biol. 2000, 10, 147-154). Mutations in Ras, which cause the protein to persistently bind GTP and thus become constitutively active, can lead to unregulated cell division; such Ras mutants are found in approximately 30% of human tumors (Bos, Ras Oncogenes in human cancer: A review. Cancer Res. 1989, 49, 4682-4689; Clark and Der, Ras proto-oncogene activation in human malignancy. In Cellular Cancer Markers; Garrett, C. T., Sell, S., Eds.; Humana Press: Totowa, N.J., 1995; pp 17-52). In the 1980s, it was reported that Ras required farnesylation to enhance its hydrophobicity and thereby facilitate its anchorage to the plasma membrane, a process necessary for its signaling function (Willumsen, et al., Harvey murine sarcoma virus p21 Ras protein: Biological and biochemical significance of the cysteine nearest the carboxy terminus. EMBO J. 1984, 3, 2581-2585; Casey, et al., p21 Ras is modified by a farnesyl isoprenoid. Proc. Natl. Acad. Sci. U.S.A. 1989, 86, 8323-8327).
The prenyltransferases are a family of zinc metallo-enzymes that catalyze the prenylation (addition of a prenyl group through a thioether linkage) of a particular set of proteins, many of which are crucial to signal transduction pathways, causing their localization to the plasma membrane and other cellular compartments and so rendering them biologically active (Liu, et al., RhoB Alteration Is Necessary for Apoptotic and Antineoplastic Responses to Farnesyltransferase Inhibitors. Mol. Cell. Biol. 2000, 20, 6105-6113). There are three members of the prenyltransferase family: farnesyltransferase (FTase), geranygeranyltransferase-I (GGTase-I), and geranygeranyltransferase-II (GGTase-II). FTase catalyzes the transfer of a farnesyl (C15 isoprenoid) group from the co-substrate farnesylpyrophosphate (FPP) to the cysteine residue within the C-terminus Cala2X tetrapeptide sequence of the target protein (including Ras and Rheb), where C=cysteine, a=an aliphatic amino acid, and X=methionine (M), serine (S), alanine (A), or glutamine (Q); (Chen, et al., Both Farnesylated and Geranylgeranylated RhoB Inhibit Malignant Transformation and Suppress Human Tumor Growth in Nude Mice. J. Biol. Chem. 2000, 275, 17974-17978). Likewise, GGTase-I catalyzes the corresponding S-geranylgeranylation by accelerating the transfer of the geranylgeranyl group (C20 isoprenoid) from GGPP to the cysteine within the C-terminus Cala2X sequence of the substrate protein (including Rho, Rap, and Ral) (Casey, Biochemistry of Protein Prenylation. Lipid Res. 1992, 33, 1731-1740), where this time X is usually leucine (L), isoleucine (I), or phenylalanine (F); (Chen, et al., Both Farnesylated and Geranylgeranylated RhoB Inhibit Malignant Transformation and Suppress Human Tumor Growth in Nude Mice. J. Biol. Chem. 2000, 275, 17974-17978). It is the identity of the X residue that dictates if a target protein is farnesylated or geranylgeranylated and is so-called the specificity residue. Finally, in a similar fashion, GGTase-II transfers two geranylgeranyl groups to protein trafficking Rab proteins that contain Cys-Cys or Cys-Ala-Cys sequences at the C-terminus (Chen, et al., Both Farnesylated and Geranylgeranylated RhoB Inhibit Malignant Transformation and Suppress Human Tumor Growth in Nude Mice. J. Biol. Chem. 2000, 275, 17974-17978).
The ability of some proteins to cause cancer depends on their modification by FT or GGT-1 with lipids called farnesyl or geranylgeranyl. Furthermore, cancer cells contain both farnesylated and geranylgeranylated cancer-causing proteins. Therefore, inhibiting FT or GGT-1 is a potential approach to combat cancer. However, inhibition of the farnesylation of some cancer-causing proteins such as K-Ras (encoded by one of the most frequently mutated cancer-causing genes in human cancers) leads to its geranylgeranylation keeping K-Ras active and rescuing cancer cells from FTI anti-tumor effects.
In addition to inhibiting FTase in vitro (Bell, Inhibitors of farnesyltransferase: A rational approach to cancer chemotherapy? Exp. Opin. Ther. Patents 2000, 10, 1813-1831), farnesyltransferase inhibitors (FTIs) have demonstrated antitumor activity in several animal models (Bell, Inhibitors of farnesyltransferase: A rational approach to cancer chemotherapy? J. Med. Chem. 2004, 8, 1869-1878). Clinically, however, the results are mixed. For example, a lack of activity was reported when Tipifarnib (R115777; Venet, et al., Farnesyl Protein Transferase Inhibitor ZARNESTRA R115777—History of a Discovery. Curr. Top. Med. Chem. 2003, 3, 1095-1102) was used against advanced colorectal and pancreatic cancers (Rao, et al. Phase III double-blind placebo-controlled study of farnesyl transferase inhibitor R115777 in patients with refractory advanced colorectal cancer. J. Clin. Oncol. 2004, 22, 3950-3957; Johnson, and Heymach, Farnesyl transferase inhibitors for patients with lung cancer. Clin. Cancer Res. 2004, 10, 4254s-4257s). In contrast, extremely encouraging results were observed when Tipifarnib was used against breast cancer in combination with cytotoxic agents (Gotlib, Farnesyltransferase inhibitor therapy in acute myelogenous leukemia. Curr. Hematol. Rep. 2005, 4, 77-84; Hunt, et al., Discovery of (R)-7-Cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine (BMS-214662), a Farnesyltransferase Inhibitor with Potent Preclinical Antitumor Activity. J. Med. Chem. 2000, 43, 3587-3595). In recent years, it has become clear that aberrant Ras activity is not the only target for FTIs, and it is likely that other FTase substrates, such as Rheb, are also involved in oncogenesis (Liu, et al., Antitumor Activity of SCH 66336, an Orally Bioavailable Tricyclic Inhibitor of Farnesyl Protein Transferase, in Human Tumor Xenograft Models and Wap-ras Transgenic Mice. Cancer Res. 1998, 58, 4947-4956; Baum and Kirschmeier, Preclinical and clinical evaluation of farnesyltransferase inhibitors. Curr. Oncol. Rep. 2003, 5, 99-107; Taveras, et al., Sch-66336 (sarasar) and other benzocycloheptapyridyl farnesyl protein transferase inhibitors: discovery, biology and clinical observations. Curr. Top. Med. Chem. 2003, 3, 1103-1114; Prendergast and Rane, N. Farnesyltransferase Inhibitors: Mechanism and Applications. Expert Opin. Invest. Drugs 2001, 10, 2105-2116). Nonetheless, despite the now-apparent complexity of this system and the unclear molecular mechanisms by which FTIs operate, the past decade has seen many FTIs established as antiproliferative agents with high efficacy and low toxicity, validating the continued research into more drug-like FTIs as alternative chemotherapeutics for cancer (Bassou, 2006, J Lipid Res; Bell, Inhibitors of farnesyltransferase: A rational approach to cancer chemotherapy? J. Med. Chem. 2004, 8, 1869-1878; Doll, et al., Farnesyltransferase inhibitors as anticancer agents: critical crossroads. Curr. Opin. Drug Discov. Devel. 2004, 7, 478-486).
Previous research has focused on the design of peptidomimetic inhibitors of FTase based on the Cala2X tetrapeptide substrate (Zhang and Casey, Protein Prenylation: Molecular Mechanisms and Functional Consequences. Annu. Rev. Biochem. 1996, 65, 241-269; Der and Cox, Isoprenoid Modification and Plasma-Membrane Association: Critical Factors for Ras Oncogenicity. Cancer Cells 1991, 3, 331-340; Ohkanda, et al. Structure-based design of imidazole-containing peptidomimetic inhibitors of protein farnesyltransferase. Org. Biomol. Chem., 2006, 4, 482-492; Qian, et al., Design and structural requirements of potent peptidomimetic inhibitors of p21ras farnesyltransferase. J. Biol. Chem. 1994, 269, 12410-12413).